Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Research into molecular targets for drug development in melanoma is starting to bear fruit. Of the drugs tested to date in patients with metastatic melanoma, those that have yielded the best results are V600E BRAF inhibitors in melanomas carrying the V600E mutation; c-kit tyrosine kinase activity inhibitors in melanomas carrying c-kit mutations; and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, which block the mechanisms involved in immune tolerance. Many problems have yet to be resolved in these areas, however, such as the rapid development of resistance to BRAF and c-kit inhibitors and the lack of biomarkers to predict treatment response in the case of CTLA-4 blockers. We review the results of targeted therapy with these and other drugs in metastatic melanoma and discuss what the future holds for this field.
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PMID:New therapeutic targets in melanoma. 2226 72

Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment.
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PMID:Profile of ipilimumab and its role in the treatment of metastatic melanoma. 2226 18

Treatment of metastatic melanoma is a challenge for clinicians as most agents have failed to demonstrate improved survival in phase III trials. Despite the immunogenicity of this tumor entity, different immunological interventions including cytokine therapy, vaccination, biochemotherapy or allogeneic hematopoietic cell transplantation did not lead to a satisfactory response. However, continuous investigation on the immune mediated rejection of melanoma cells has led to the development of effective antibodies blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical negative regulator of the antitumor T-cell response. Based on data from rodent models, the anti-CTLA-4 antibody ipilimumab was developed into clinical studies where it had encouraging activity in advanced melanoma with unusual response patterns. As in most immunostimulatory therapies, acute toxicities were severe and clearly mechanism-related. Although some patients developed signs of autoimmunity, the toxicities were overall manageable and mostly reversible. This review summarizes different immunotherapeutical approaches against melanoma that have been applied in the past and focuses on CTLA-4 blockade with respect to its mechanism, clinical effectiveness and immunological side effects.
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PMID:Immunotherapy for malignant melanoma. 2232 80

Ipilimumab is a U.S. Food and Drug Administration-approved novel T-cell potentiator that improves survival in metastatic melanoma. Ipilimumab blocks cytotoxic T-lymphocyte antigen-4, a negative regulator of the immune response, thus promoting T-cell activation and prolonging a patient's antitumor response. However, that action may produce a mechanism-related spectrum of immune-related adverse events (irAEs), which can become severe and life-threatening if left unrecognized and untreated. This article describes the clinical properties of ipilimumab, specifically in regard to its unique profile of irAEs. Guidelines to manage irAEs are reviewed with a particular emphasis on the contribution of nurses to patient care and education. The nurse's role in facilitating communication among the oncology team, primary practice team, patients, and caregivers is fundamental to early recognition and effective management of irAEs so that patients can continue on therapy. As a regular, ongoing presence in patient care, the oncology nurse is well placed to deliver information, assess patients' understanding of that information, and support them through their cancer experience. Checklists of irAE symptoms may be useful for patients and nurses alike. In addition, education on ipilimumab's mechanism of action and how it contributes to irAEs should form an integral part of the patient treatment plan.
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PMID:Managing immune-related adverse events to ipilimumab: a nurse's guide. 2245 39

Clinical activity of anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) monoclonal antibodies (mAb) has changed the approaches for the treatment of cancer in terms of patterns of response, duration of response, and adverse event profiles. In fact, antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including anti-tumor immunity. Two recent studies using ipilimumab (an anti-CTLA-4 mAb) demonstrated improvements in overall survival in the treatment of advanced melanoma. These studies utilized two different schedules of treatment in different patient categories (first and second line of treatment). However, the results were quite similar despite the different dosage used and the combination with dacarbazine in the first line treatment. Ongoing clinical studies will establish the efficacy of ipilimumab as monotherapy or in combination with other drugs for the treatment of metastatic melanoma and a variety of other cancers. Other antibodies, such as CD137 agonists and PD-1 antagonists, are currently in various stages of pre-clinical and clinical development. Agonist antibodies directed against CD137 (4-1BB) on the surface of antigen-primed T-lymphocytes increase tumor immunity that is curative against some transplantable murine tumors. Programmed death-1 (PD1) is a surface molecule delivering inhibitory signals important to maintain T-cell functional silence against their cognate antigens. Interference with PD1 or its ligand PD-L1 (B7-H1) increases anti-tumor immunity. As a result, human mAbs anti-PD1 and anti-PD-L1 are under clinical development. This paper reviews recent studies in the treatment of advanced melanoma with these types of monoclonal antibodies. Ipilimumab can be considered a cornerstone of a new era in melanoma treatment. However, the aim is to optimize the therapy with anti-CTLA-4 antibodies to define the best schedule for next combination regimens (other immunomodulatory antibodies, BRAF/MEK inhibitors, vaccines, etc.) that represent the natural evolution of future melanoma therapy.
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PMID:Immunomodulating antibodies in the treatment of metastatic melanoma: the experience with anti-CTLA-4, anti-CD137, and anti-PD1. 2252 73

Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)-ipilimumab and tremelimumab-have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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PMID:Management of immune-related adverse events and kinetics of response with ipilimumab. 2261 89

Malignant melanoma is a tumor of the melanocytes of the skin with different types, that can metastasize to many organs including the brain at the advanced stages. Metastasis to brain is most dreadful complication, and at times untreatable as it's noted in the late stages. Therefore, tremendous effort has been made in the past decades to treat metastatic melanoma patients more efficiently. Although chemotherapy is one of the treatment options, it also interferes with all rapidly dividing cells including the non-cancerous cells; therefore one should consider the side effects. As there is lot of evidence that melanoma is immunogenic, a concept of immunotherapy has risen. Immunotherapy uses molecules of the body's own immune system and disrupts the growth of cancer cells has gained a lot of attention in the past two decades. Adoptive cell therapies (ACT), vaccines, viruses, and cytokine administration in immunotherapy stimulate T cells to recognize and destroy the cancer cells. This article is a brief review of various molecules and strategies that are currently used in immunotherapy against malignant melanoma. These include the anti-Cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, cytokine administration, vaccine therapy, oncolytic viruses, adoptive cell therapy, and inhibitor of STAT3 activation.
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PMID:A role of immunotherapy in metastatic malignant melanoma. 2269 95

Immunotherapy using unspecific modulators has a long tradition in the adjuvant treatment of stage II/III melanoma. Interferon has shown a consistent effect on relapse-free survival independent of interferon dosage and duration. The results of the american Joint Committee on Cancer (AJCC) Melanoma Staging Database analysis led to a strict inclusion of additional prognostic risk factors such as ulceration of the primary and microscopic lymph node involvement explored by the sentinel node biopsy in the revised 2009 AJCC classification. These factors are now being increasingly included as stratification factors into clinical trials and yield a new hypothesis that primarily patients with both characteristics benefit from adjuvant interferon treatment. In the metastatic situation, interleukin-2 is the only immunotherapeutic agent approved by the Food and Drug administration. In combination with interferon and/or with various chemotherapeutic agents, IL-2 is associated with substantial toxic effect and poor efficacy that does not improve overall survival (OS). Ipilimumab is a fully human, monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 and has recently been approved for metastatic melanoma based on two independent randomized phase III studies both demonstrating an improved OS rate after 1, 2, and 3 years compared with the control group. Based on this major step in treating metastatic melanoma, novel adjuvant strategies in stage III and combination therapies with targeted agents in stage IV are currently being explored.
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PMID:Advances and perspectives in immunotherapy of melanoma. 2298 43

Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4 and has become the first immune checkpoint inhibitor to enter clinical practice, being recently approved for the treatment of metastatic melanoma. Immune toxicity due to ipilimumab causing colitis, hepatitis, dermatitis and hypophysitis is well-described. We report on a case of acute renal failure resolving rapidly with high-dose corticosteroid treatment highlighting the importance of vigilance for rarer immune-related toxicities as clinical experience with ipilimumab grows.
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PMID:Ipilimumab-induced immune-related renal failure--a case report. 2306 May 94

Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Lymphocytic and granulomatous hypophysitis are the most common forms, but new variants have recently been reported such as IgG4-related hypophysitis that is identified by well-defined criteria. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. Monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), investigated in metastatic melanoma, can induce hypophysitis. Hypophysitis's pathogenesis remains obscure but several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool.
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PMID:[Hypophysitis: increasingly complex clinicopathological spectrum!]. 2308 77


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